PERSISTENT CD3-CROSS-LINKING DOWN-REGULATES INTERLEUKIN-2 RESPONSIVENESS IN INTERLEUKIN-2-COMPETENT CLONED T-CELLS - THE POSSIBLE INVOLVEMENT OF PROTEIN-KINASE-C

To investigate the regulation of interleukin-2 (IL-2) responsiveness o f T cells, a human CD4(+) T-cell clone with constitutive expression of IL-2 receptors was stimulated with recombinant IL-2 (rIL-2) in the pr esence or absence of immobilized anti-CD3 monoclonal antibodies (alpha CD3(imm) MoAb). Incubation of T cells with alpha CD3(imm) MoAb decrea sed IL-2-induced proliferation which could not be ascribed to the modu lation of IL-2 receptor expression nor to cell death. Phorbol-myristat e-acetate (PMA), an activator of protein kinase C (PKC), also induced down-regulation of IL-2 responsiveness. The alpha CD3(sol) MoAb, induc ing Ca2+-mobilization without activating PKC, did not inhibit IL-2 res ponsiveness whereas cyclosporine A (CsA), a drug that inhibits the Ca2 +-dependent activation pathway, did not prevent the induction of IL-2 hyporesponsiveness induced by alpha CD3(imm) MoAb. It is concluded tha t modulation of IL-2 responsiveness of T cells via the T-cell receptor /CD3 complex (TCR/CD3) may be mediated by a PKC-activating signal.